Field of the Invention
The present invention is in the field of lung cancer biology and the diagnosis and prognosis thereof. More specifically, the present invention relates to certain microRNA and small nucleolar RNA biomarkers useful in the early diagnosis and prognosis of lung cancer.
Description of the Related Art
Lung cancer is the number one cancer killer in the USA and worldwide (1). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Tobacco smoking is the major cause of the disease. The overall 5-year survival rate for stage I NSCLC patients who are typically treated with surgery remains up to 83%. In contrast, only 5-15% and less than 2% of patients with stage III and IV NSCLC are alive after five years (1). These statistics provide the primary rationale to improve NSCLC early detection. Recently, a NCI-National Lung Screening Trail (NLST) showed that the early detection of lung cancer by using low-dose computed tomography (LDCT) significantly reduced the mortality (2). However, 25% of smokers screened by LDCT have indeterminate pulmonary nodules (PNs), of which 95% are determined to be false-positives. Given the high-false positive rate of LDCT, there is large number of referrals for invasive biopsies that carry their own morbidity and mortality, and expensive 2-year multiple follow-up examinations. It is clinically important to develop noninvasive modalities that can accurately identify early stage lung cancer in a safe and cost-effective manner, so that smokers with benign growths can be spared from the biopsies and follow-up examinations, while effective treatments can be immediately initiated for NSCLC (3).
Blood-based biomarkers have been developed for lung cancer early detection and diagnosis. However, blood is a circulating body fluid, molecular changes that can be detected in blood may not specifically associated with lung cancer. Therefore, blood-based biomarkers have a low specificity for lung cancer early detection and diagnosis. In contrast sputum is a noninvasively and easily accessible body fluid that contains exfoliated bronchial epithelial cells (4). Cytological study of sputum can identify morphological abnormalities of bronchial epitheliums, and thus is used for noninvasive diagnosis of lung cancer. However, sputum cytology has a poor sensitivity for detection of lung cancer at the early stage. Molecular study of sputum could detect the molecular abnormalities in the large bronchial airways that reflect those existing in primary lung tumors. Therefore, the analysis of sputum for the molecular changes may provide a noninvasive approach for diagnosis of lung cancer.
Non-coding RNAs (ncRNAs) molecules can regulate a wide range of biological processes, including chromatin remodeling, gene transcription, mRNA translation, and protein function (5). Based on length or number of nucleotides (nts), ncRNAs are divided into three categories (6). First, small ncRNAs are 17-30 nts in length and include microRNAs (miRNAs), piwi-interacting RNAs, and transcription initiation RNAs. Second, middle-size ncRNAs are typically 20 and 200 nts in length and mainly consist of small nucleolar RNAs (snoRNAs). Third, long ncRNAs (IncRNAs) are over 200 nts, which comprise several well-characterized ncRNAs, such as XIST and H19 (7).
It is well documented that dysregulation of miRNAs plays a crucial role in tumorigenesis. Furthermore, new and unexpected functions of middle-size ncRNAs and IncRNAs have been discovered recently, which have highly and actively diverse roles in the processes of carcinogenesis than previously thought (8-15). For example, snoRA42, a middle-size ncRNA, has oncogenic function in the development and progression of NSCLC (10-11). Upregulation of snoRA42 could contribute to lung tumorigenesis by regulating features of tumor-initiating cells (10). Small and middle-size ncRNAs are reproducibly detectable in sputum (16-20).
Therefore, there is a recognized need in the art for the development of the cancer-related non-coding RNAs as potential biomarkers for the detection of malignancies. The prior art is deficient in cancer-related ncRNAs and in methods of using the same for the early diagnosis of and prognosis of cancer. The present invention fulfills this longstanding need and desire in the art.